CN106995446B - Preparation method of Bruton's tyrosine kinase inhibitor - Google Patents
Preparation method of Bruton's tyrosine kinase inhibitor Download PDFInfo
- Publication number
- CN106995446B CN106995446B CN201610045393.7A CN201610045393A CN106995446B CN 106995446 B CN106995446 B CN 106995446B CN 201610045393 A CN201610045393 A CN 201610045393A CN 106995446 B CN106995446 B CN 106995446B
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction solvent
- ethyl acetate
- reaction
- phenoxyphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to the field of drug synthesis, in particular to a preparation method of a Bruton's tyrosine kinase inhibitor. The novel process is characterized in that 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine and (S) -tert-butyloxycarbonyl-3-hydroxypiperidine react in a dark place under the action of triphenylphosphine and diisopropyl azodicarboxylate, then Boc is removed to form salt under an acidic condition, and finally, 25% NaOH is used for decomposing salt and crystallizing in one pot to prepare an intermediate I, and the intermediate I reacts with acryloyl chloride to generate a target product under an alkaline condition.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a Bruton tyrosine kinase inhibitor.
Background
The Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one was developed by a combination of Pharmacyclics and Qiangsheng under the trade name Imbruvica and Ibrutinib. It is an innovative oral drug named Bruton's Tyrosine Kinase (BTK) inhibitor, mainly used for the treatment of a rare invasive blood cancer, Mantle Cell Lymphoma (MCL). The drug can irreversibly inhibit BTK through selective covalent binding with cysteine residue of active site of target protein Btk, thereby effectively preventing tumor from migrating from B cell to lymphoid tissue adapted to tumor growth environment.
The synthesis of this drug is reported in patent WO2014022390a 1. The process comprises the steps of taking 4-amino-1H-pyrazolo (3,4-d) pyrimidine as a raw material, halogenating, reacting with alcohols under the action of potassium permanganate and palladium reagents to obtain an intermediate 2, reacting the intermediate 2 with (S) -tert-butyloxycarbonyl-3-hydroxypiperidine under the action of triphenylphosphine and diisopropyl azodicarboxylate to generate an intermediate 3, separating by column chromatography to obtain a pure intermediate 3, introducing hydrochloric acid gas into the intermediate 3 to remove Boc and form salt, and directly reacting with acryloyl chloride without dissolving salt to generate a crude product.
The synthetic route is as follows:
in the process, a palladium reagent which is difficult to remove and expensive is used, column chromatography analysis is used for many times, the steps are complicated, the process is complex, the production cost is high, and the industrial production is not facilitated.
Disclosure of Invention
The technical problem to be solved by the invention is to avoid using a palladium reagent, simplify test steps, simplify operation, complete a one-pot method, avoid column chromatography separation as much as possible, and provide a simple and effective method for preparing Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propylene-1-one.
The technical scheme of the invention is summarized as follows:
a method for preparing Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one, which comprises the following steps:
a. mixing (S) -tert-butyloxycarbonyl-3-hydroxypiperidine, a reaction solvent and triphenylphosphine, stirring and dissolving to be clear, and adding 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine;
b. adding diisopropyl azodicarboxylate dropwise in a dark place, and stirring for reaction;
c. removing Boc salt under acidic condition;
d. adding purified water, and extracting with chloroform and ethyl acetate to remove impurities;
e. using 25% NaOH to dissolve salt and crystallize in one pot to prepare an intermediate I;
f. the intermediate I is dissolved in a reaction solvent and reacts with acryloyl chloride under alkaline conditions.
In the step a, the reaction solvent is selected from one of DMF, dichloromethane, ethyl acetate, ethanol, styrene, perchloroethylene, glacial acetic acid, trichloroethylene, THF, acetone, ethylene glycol ether and triethanolamine; preferably, the reaction solvent is selected from one of DMF, acetone and ethyl acetate; further preferred is ethyl acetate.
And (b) the dosage of the reaction solvent in the step (a) is 9-15 times of that of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine in terms of volume-mass ratio mL/g.
And (b) dropwise adding diisopropyl azodicarboxylate at the temperature of 10-15 ℃.
B, after dropwise adding diisopropyl azodicarboxylate, stirring and reacting at the temperature of 20-30 ℃; the stirring reaction time is 2-5 h.
C, dropwise adding concentrated hydrochloric acid at 0 ℃ to adjust the pH value to 2.0-3.0 under the acidic condition; and dropwise adding concentrated hydrochloric acid to react for 3-5 h at room temperature.
And d, the amount of the purified water added in the step d is 9-15 times of that of the 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine in terms of volume-mass ratio mL/g.
Step e 25% NaOH was added under ice-water bath conditions.
And e, when the salt is dissolved and crystallized, naturally heating to room temperature to start crystallization, wherein the crystallization time is 5-8 h.
The molar ratio of the intermediate I to the acryloyl chloride in the step f is 1: 0.9-1.05.
Adding triethylamine, ammonia water, sodium hydroxide, sodium ethoxide, ethylenediamine, isopropylamine, n-butylamine, diethylamine and diisopropanolamine under the alkaline condition; one of triethylamine, diethylamine and diisopropanolamine is preferably added, and diethylamine is more preferably added.
The reaction solvent in the step f is selected from one of DMF, ethanol, styrene, perchloroethylene, glacial acetic acid, dichloromethane, trichloroethylene, THF, acetone, ethyl acetate, ethylene glycol ether and triethanolamine, trichloromethane, acetonitrile and toluene; preferably, the reaction solvent is selected from one of DMF, acetone, ethyl acetate and ethylene glycol ether; further preferred is ethyl acetate.
And f, diluting the acryloyl chloride by 20-30 times with a reaction solvent.
And f, dripping the acryloyl chloride for 1-2 h.
F, after the dropwise addition of the acryloyl chloride is finished, the reaction temperature is 25-30 ℃; the reaction time is 1-3 h.
The invention has the advantages that: the reaction takes 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine as a starting material to react with (S) -tert-butyloxycarbonyl-3-hydroxypiperidine, Boc is removed under an acidic condition, salt is formed, and the intermediate I is prepared by one pot of salt decomposition, so that the method has the advantages of simple steps, simple operation, low cost of used reagents, high yield of more than 85 percent and high purity of more than 99 percent.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The starting materials or reagents used in the examples are commercially available.
Example 1
Preparation of intermediate I
Adding 600g of (S) -tert-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3LDMF into a reaction bottle, stirring for dissolving, adding 300g of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine after dissolving, continuing stirring for 10-30 min, keeping out of the sun, controlling the temperature to be 10-15 ℃, starting dropwise adding diisopropyl azodicarboxylate, heating to 25-30 ℃ after dropwise adding, and stirring for reacting for 3-4H; stopping the reaction, cooling to 0 ℃, starting to dropwise add 1110mL of concentrated HCl, heating to room temperature after dropwise addition, and stirring for reaction for 3-4 h; stopping reaction, adding 3L of purified water, stirring, then respectively adding 1.8L of chloroform for extraction for 5 times and 1.8L of ethyl acetate for extraction for 2 times, after extraction is finished, adding 1.2L of ethyl acetate, cooling to 0 ℃, starting to dropwise add a 25% NaOH solution, adjusting the pH value to 8-9, precipitating a large amount of solid, stirring for crystallization, finishing crystallization, centrifugally throwing and filtering, washing a filter cake with a small amount of ethyl acetate, and performing vacuum drying on the obtained filter cake at 55-60 ℃ under the vacuum degree of-0.080 MPa to-0.100 MPa to obtain 336.4g of an intermediate I, wherein the yield is 88.0%.
Preparation of di, Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one
Adding 200g of the intermediate I and 600mL of DMF into a reaction bottle, stirring, adding 216mL of triethylamine, stirring for dissolving, stirring for 20-30 min, starting dropwise adding 1044.3mL of dichloromethane solution containing 44.3mL of acryloyl chloride at room temperature, controlling for 1-1.5 h, controlling the temperature to be 25-30 ℃ for reaction after dropwise adding, controlling the temperature to be 25-30 ℃ for reaction for 1.5-2 h after dropwise adding, adding 5% of dilute hydrochloric acid for washing after the reaction is finished, controlling the pH to be 5-6, respectively washing twice with sodium bicarbonate and 120mL of saturated saline water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 209.5g of solid, wherein the yield is 92.2% and the purity is 99.1%.
Example 2
Preparation of intermediate I
Adding 600g of (S) -tert-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of acetone into a reaction bottle, stirring for dissolving, adding 300g of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine after dissolving, continuing stirring for 10-30 min, keeping out of the sun, controlling the temperature to be 10-15 ℃, starting to dropwise add diisopropyl azodicarboxylate, heating to 25-30 ℃ after dropwise adding, and stirring for reacting for 3-4H; stopping the reaction, cooling to 0 ℃, starting to dropwise add 1110mL of concentrated HCl, heating to room temperature after dropwise addition, and stirring for reaction for 3-4 h; stopping reaction, adding 3L of purified water, stirring, then respectively adding 1.8L of chloroform for extraction for 5 times and 1.8L of ethyl acetate for extraction for 2 times, after extraction is finished, adding 1.2L of ethyl acetate, cooling to 0 ℃, starting to dropwise add a 25% NaOH solution, adjusting the pH value to 8-9, precipitating a large amount of solids, stirring for crystallization, finishing crystallization, centrifugally throwing and filtering, washing a filter cake with a small amount of ethyl acetate, and performing vacuum drying on the obtained filter cake at 55-60 ℃ under the vacuum degree of-0.080 MPa to-0.100 MPa to obtain 328.7g of an intermediate I and the yield of 86.1%.
Preparation of di, Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one
Adding 200g of the intermediate I and 800mL of acetone into a reaction bottle, stirring, adding 216mL of triethylamine, stirring for dissolving, stirring for 20-30 min, starting dropwise adding 1044.3mL of an ethyl acetate solution containing 44.3mL of acryloyl chloride at room temperature, controlling the time for 1-1.5 h, controlling the temperature to react at 25-30 ℃, controlling the temperature to react for 1.5-2 h at 25-30 ℃ after dropwise adding, adding 5% of dilute hydrochloric acid for washing after the reaction is finished, controlling the pH to be 5-6, respectively washing twice with sodium bicarbonate and 120mL of saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 207.2g of a solid, wherein the yield is 91.0%, and the purity is 99.7%.
Example 3
Preparation of intermediate I
Adding 600g of (S) -tert-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of ethyl acetate into a reaction bottle, stirring for dissolving, adding 300g of 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine after dissolving, continuing stirring for 10-30 min, keeping out of the sun, controlling the temperature to be 10-15 ℃, starting to dropwise add diisopropyl azodicarboxylate, heating to 25-30 ℃ after dropwise adding, and stirring for reacting for 3-4H; stopping the reaction, cooling to 0 ℃, starting to dropwise add 1110mL of concentrated HCl, heating to room temperature after dropwise addition, and stirring for reaction for 3-4 h; stopping reaction, adding 3L of purified water, stirring, then respectively adding 1.8L of chloroform for extraction for 5 times and 1.8L of ethyl acetate for extraction for 2 times, after extraction is finished, adding 1.2L of ethyl acetate, cooling to 0 ℃, starting to dropwise add a 25% NaOH solution, adjusting the pH value to 8-9, precipitating a large amount of solids, stirring for crystallization, finishing crystallization, centrifugally throwing and filtering, washing a filter cake with a small amount of ethyl acetate, and performing vacuum drying on the obtained filter cake at 55-60 ℃ under the vacuum degree of-0.080 MPa to-0.100 MPa to obtain 336.3g of an intermediate I, wherein the yield is 88.1%.
Preparation of di, Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one
Adding 200g of the intermediate I and 800mL of ethyl acetate into a reaction bottle, stirring, adding 216mL of triethylamine, stirring for dissolving, stirring for 20-30 min, starting dropwise adding 1044.3mL of THF solution containing 44.3mL of acryloyl chloride at room temperature, controlling the reaction time to be 1-1.5 h, controlling the temperature to be 25-30 ℃ after the dropwise adding is finished, reacting for 1.5-2 h at the temperature of 25-30 ℃, adding 120mL of 5% diluted hydrochloric acid for washing after the reaction is finished, controlling the pH to be 5-6, respectively washing twice with sodium bicarbonate and 120mL of saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 212.7g of a solid, wherein the yield is 93.4% and the purity is 99.5%.
Comparative example 1
The reaction solvent DMF from step one, intermediate I preparation in example 1 was replaced by chloroform; the reaction solvent for the preparation of Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one, step two in example 1, was replaced with chloroform. The final yield was 76.2% and the purity was 91.6%.
Comparative example 2
101mg of 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine and 330mg of polymer-linked Triphenylphosphine (TPP) (polymerlab) were mixed together with 5mL of Tetrahydrofuran (THF). To the resulting mixture were added tert-butyl 3-hydroxypiperidine-1-carboxylate (200 mg; 2.0 equivalents) and diisopropyl azodicarboxylate (0.099mL) in that order. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the resin and the reaction mixture was concentrated and then purified by flash chromatography (pentane/ethyl acetate 1/1) to give intermediate 3(55 mg).
Intermediate 3(48.3mg) was treated with 1mL of 4 NHCL/dioxane solution for 1 hour and then concentrated to dryness. The residue was dissolved in dichloromethane and triethylamine (0.042mL) was added followed by acryloyl chloride (0.010 mL). The reaction was terminated after 2 hours. The reaction mixture was washed with 5% by weight aqueous citric acid solution and then with brine. The organic layer was dried over MgSO4 and concentrated and purified by flash chromatography (using CH)2CL2/MeOH — 25/1) to give 22mg of compound 4 as a white solid.
Claims (19)
1. A preparation method of bruton's tyrosine kinase inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one, which is characterized by comprising the following steps:
a, (S) -tert-butyloxycarbonyl-3-hydroxypiperidine, a reaction solvent and triphenylphosphine are mixed, stirred and dissolved to be clear, and 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine is added;
b, keeping out of the sun, controlling the temperature to be 10-15 ℃, starting to dropwise add diisopropyl azodicarboxylate, and stirring for reaction;
c, dropwise adding concentrated hydrochloric acid at 0 ℃ to adjust the pH value to 2.0-3.0, reacting at room temperature for 3-5 h after dropwise adding the concentrated hydrochloric acid, and removing Boc salifying;
d, adding purified water, and extracting and removing impurities by using trichloromethane and ethyl acetate;
e, using 25% NaOH to perform salt decomposition and crystallization in one pot to prepare an intermediate I;
and f, dissolving the intermediate I in a reaction solvent, and reacting with acryloyl chloride under an alkaline condition.
2. The method according to claim 1, wherein in step a, the reaction solvent is one selected from the group consisting of DMF, dichloromethane, ethyl acetate, ethanol, styrene, perchloroethylene, glacial acetic acid, trichloroethylene, THF, acetone, ethylene glycol ether and triethanolamine.
3. The method according to claim 1, wherein the reaction solvent in step a is one selected from DMF, acetone and ethyl acetate.
4. The method according to claim 1, wherein the reaction solvent in step a is ethyl acetate.
5. The preparation method of claim 1, wherein the amount of the reaction solvent in the step a is 9 to 15 times that of the 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine in terms of volume to mass ratio mL/g.
6. The preparation method according to claim 1, wherein the temperature for the dropwise addition of diisopropyl azodicarboxylate in step b is 20-30 ℃ under stirring; the stirring reaction time is 2-5 h.
7. The preparation method of claim 1, wherein the amount of the purified water added in the step d is 9 to 15 times of that of the 4-amino-3- (4-phenoxyphenyl) -1H-pyrido (3,4-d) pyrimidine in terms of volume to mass ratio mL/g.
8. The method of claim 1, wherein step e comprises adding 25% NaOH under ice-water bath conditions.
9. The preparation method according to claim 1, wherein during the salt-dissolving and crystallization in the step e, the temperature is naturally raised to room temperature to start crystallization, and the crystallization time is 5-8 h.
10. The preparation method according to claim 1, wherein the molar ratio of the intermediate I to the acryloyl chloride in the step f is 1: 0.9-1.05.
11. The method of claim 1, wherein the basic condition in step f is triethylamine, ammonia water, sodium hydroxide, sodium ethoxide, ethylenediamine, isopropylamine, n-butylamine, diethylamine, diisopropanolamine.
12. The method of claim 1, wherein the basic condition in step f is the addition of one of triethylamine, diethylamine and diisopropanolamine.
13. The method of claim 1, wherein the basic condition in step f is the addition of diethylamine.
14. The method according to claim 1, wherein the reaction solvent in step f is one selected from the group consisting of DMF, ethanol, styrene, THF, perchloroethylene, glacial acetic acid, dichloromethane, trichloroethylene, acetone, ethyl acetate, ethylene glycol ether, triethanolamine, trichloromethane, acetonitrile and toluene.
15. The method of claim 1, wherein the reaction solvent in step f is one selected from DMF, acetone, ethyl acetate and ethylene glycol ether.
16. The method according to claim 1, wherein the reaction solvent in step f is ethyl acetate.
17. The method according to claim 1, wherein the acryloyl chloride in step f is diluted 20 to 30 times with the reaction solvent.
18. The preparation method according to claim 1, wherein the dropping time of the acryloyl chloride in the step f is 1-2 h.
19. The preparation method according to claim 1, wherein the reaction temperature is 25-30 ℃ after the dropwise addition of acryloyl chloride in the step f is finished; the reaction time is 1-3 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610045393.7A CN106995446B (en) | 2016-01-22 | 2016-01-22 | Preparation method of Bruton's tyrosine kinase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610045393.7A CN106995446B (en) | 2016-01-22 | 2016-01-22 | Preparation method of Bruton's tyrosine kinase inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106995446A CN106995446A (en) | 2017-08-01 |
| CN106995446B true CN106995446B (en) | 2021-07-02 |
Family
ID=59428396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610045393.7A Active CN106995446B (en) | 2016-01-22 | 2016-01-22 | Preparation method of Bruton's tyrosine kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106995446B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116593B (en) * | 2019-11-27 | 2020-11-24 | 河北合佳医药科技集团股份有限公司 | Continuous preparation method of imatinib |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101674834A (en) * | 2007-03-28 | 2010-03-17 | 环状药物公司 | inhibitors of bruton's tyrosine kinase |
| CN102656173A (en) * | 2009-10-12 | 2012-09-05 | 药品循环公司 | Inhibitors of Bruton's tyrosine kinase |
| CN102887900A (en) * | 2006-09-22 | 2013-01-23 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN104844609A (en) * | 2015-05-12 | 2015-08-19 | 杭州和正医药有限公司 | Double-site irreversible Brutons tyrosine kinase inhibitor |
| US20150307500A1 (en) * | 2007-12-27 | 2015-10-29 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
-
2016
- 2016-01-22 CN CN201610045393.7A patent/CN106995446B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887900A (en) * | 2006-09-22 | 2013-01-23 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN101674834A (en) * | 2007-03-28 | 2010-03-17 | 环状药物公司 | inhibitors of bruton's tyrosine kinase |
| US20150307500A1 (en) * | 2007-12-27 | 2015-10-29 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
| CN102656173A (en) * | 2009-10-12 | 2012-09-05 | 药品循环公司 | Inhibitors of Bruton's tyrosine kinase |
| CN104844609A (en) * | 2015-05-12 | 2015-08-19 | 杭州和正医药有限公司 | Double-site irreversible Brutons tyrosine kinase inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106995446A (en) | 2017-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6347396B2 (en) | Novel heterocycle-containing amino acid compounds and uses thereof | |
| CN103833593B (en) | A kind of preparation method of N-(the 9-fluorenylmethyloxycarbonyl)-O-tert-butyl group-TYR | |
| CN111170892B (en) | Synthesis method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) | |
| CN107474107B (en) | Process for the preparation of GLYX-13 and compounds useful for the preparation of GLYX-13 | |
| CN101426795B (en) | Process for preparing dorzolamide | |
| CN111646998B (en) | Synthesis method of ibrutinib | |
| CN106459150A (en) | Method for producing synthetic pentapeptide | |
| CN106995446B (en) | Preparation method of Bruton's tyrosine kinase inhibitor | |
| CN105712919A (en) | Application of amide condensing agent in vildagliptin synthetic method | |
| CN104530006B (en) | The preparation method of Lansoprazole | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN103539832B (en) | A kind of improved method of bortezomib technique | |
| CN108558890A (en) | A kind of silaenafil intermediate synthetic method | |
| EP2643308B1 (en) | Process for the preparation of taurolidine and its intermediates thereof | |
| CN111116593B (en) | Continuous preparation method of imatinib | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN104016954A (en) | Method for preparing and purifying nebivolol intermediate | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN104529924B (en) | The preparation method of 5-cyclopropyl-4-[2-methylthio group-4-(trifluoromethyl) benzoyl] isoxzzole | |
| CN110015978B (en) | Synthesis method of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine | |
| JP2019505487A (en) | Method for producing long-chain compound | |
| CN113185552A (en) | Preparation method of propane fumarate tenofovir disoproxil degradation impurity | |
| CN113278021A (en) | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of Bruton tyrosine kinase inhibitor Effective date of registration: 20211224 Granted publication date: 20210702 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20221028 Granted publication date: 20210702 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of Bruton tyrosine kinase inhibitor Effective date of registration: 20221103 Granted publication date: 20210702 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980020531 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |